A man was shot and wounded on board the bus around 1 a.m. Thursday at Broad and Chestnut streets, a block south of City Hall.
The shooter was able to get away.
Authorities don't have a clear motive or description of the shooter, but are asking passengers to come forward to provide information that could help with the investigation.
"There were 15 passengers on the bus ... all the other passengers fled so we don't have any witnesses," said Chief Inspector Scott Small.
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Police said the bus driver heard several gunshots and immediately stopped the bus and opened the doors.
The driver was left behind with the 29-year-old victim who was bleeding heavily while slipping in and out of consciousness, police said.
Investigators said the victim was shot in the left side of his chest and was rushed to Jefferson University Hospital in critical condition.
"We know the shooting happened on the bus, inside the bus. We found one spent shell casing on the floor in the rear of the bus. We also found a loaded magazine, a clip on the floor in the rear of the bus," said Chief Inspector Scott Small.
Police also found a shell casing outside the bus, but they believe it was kicked off the vehicle while passengers were running to safety.
Central Detectives are working the case along with SEPTA police.
This is not the first time gun violence unfolded on the transit system in recent months.
In June, a gunman was found dead on train tracks after he shot someone on the Market Frankford Line.
Last Christmas Eve, a stray bullet narrowly missed a SEPTA bus driver in Kensington.
"It doesn't make me feel different about SEPTA, it makes me feel different about people. People are the ones that are doing this, it's not SEPTA," said rider Paulette Merritt.
Any with information should contact police at 215-686-TIPS.